application): In both mice and humans the neuroendocrine melanocortin system has been linked to weight regulation and obesity. Of the multiple receptor subtypes involved, the melanocortin-4 receptor subtype (MC4R), which is located entirely in the central nervous system, appears to play an important role in body weight homeostasis. This is suggested most strongly by knockout and mutational studies in animals. Endogenous agonists for this receptor include proopiomelanocortin-derived peptides, whereas the agouti-related protein is a natural antagonist. However, based on the use of available agonists and antagonists, function of the MC4R is difficult to distinguish from that of other melanocortin receptor subtypes, especially MC3R, for which a function has not been defined. This lack of specificity in reagents makes it difficult to assess structure-function relationships of MC4R, and to differentiate its functions from those of MC3R. Thus, the overall goal of this proposal is to develop new peptide and non-peptide MC4R probes that can be used to define the function of the MC4R, both in vitro and in vivo.
The specific aims are to 1) identify selective MC4R agonists and antagonists using peptide libraries and a combinatorial chemistry approach, 2) identify structural features of a constitutively active MC4R that will allow differentiation between agonist and antagonist behavior of ligands, and 3) test available parenteral and potential orally active compounds selective for MC4R in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057080-04
Application #
6637170
Study Section
Special Emphasis Panel (ZRG1-SSS-Z (01))
Program Officer
Sechi, Salvatore
Project Start
2000-08-15
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
4
Fiscal Year
2003
Total Cost
$292,174
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D et al. (2016) Comparative Functional Alanine Positional Scanning of the ?-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors. ACS Chem Neurosci 7:984-94
Hinkle, Patricia M; Serasinghe, Madhavika N; Jakabowski, Andrea et al. (2011) Use of chimeric melanocortin-2 and -4 receptors to identify regions responsible for ligand specificity and dependence on melanocortin 2 receptor accessory protein. Eur J Pharmacol 660:94-102
Irani, Boman G; Xiang, Zhimin; Yarandi, Hossein N et al. (2011) Implication of the melanocortin-3 receptor in the regulation of food intake. Eur J Pharmacol 660:80-7
Xiang, Zhimin; Proneth, Bettina; Dirain, Marvin L et al. (2010) Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist. Biochemistry 49:4583-600
Singh, Anamika; Haslach, Erica M; Haskell-Luevano, Carrie (2010) Structure-activity relationships (SAR) of melanocortin and agouti-related (AGRP) peptides. Adv Exp Med Biol 681:1-18
Rowland, Neil E; Schaub, Jay W; Robertson, Kimberly L et al. (2010) Effect of MTII on food intake and brain c-Fos in melanocortin-3, melanocortin-4, and double MC3 and MC4 receptor knockout mice. Peptides 31:2314-7
Atalayer, Deniz; Robertson, Kimberly L; Haskell-Luevano, Carrie et al. (2010) Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors. Am J Physiol Regul Integr Comp Physiol 298:R1667-74
Schaub, Jay W; Bruce, Erin B; Haskell-Luevano, Carrie (2010) Drugs, exercise, and the melanocortin-4 receptor-- different means, same ends: treating obesity. Adv Exp Med Biol 681:49-60
Joseph, Christine G; Yao, Hua; Scott, Joseph W et al. (2010) ??-Melanocyte stimulation hormone (??-MSH) truncation studies results in the cautionary note that ??-MSH is not selective for the mouse MC3R over the mouse MC5R. Peptides 31:2304-13

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